Antinociceptive and Cytotoxic Activity of Opioid Peptides with Hydrazone and Hydrazide Moieties at the C-Terminus.

Jolanta Dyniewicz,Piotr Kosson,Aleksandra Misicka,Joanna Matalińska,Piotr F J Lipiński,Marta Bochyńska-Czyż

doi:10.3390/molecules25153429

Abstract

In the present contribution, we analyze the influence that C-terminal extension of short opioid peptide sequences by organic fragments has on receptor affinity, in vivo analgesic activity, and antimelanoma properties. The considered fragments were based on either N-acylhydrazone (NAH) or N′-acylhydrazide motifs combined with the 3,5-bis(trifluoromethyl)phenyl moiety. Eleven novel compounds were synthesized and subject to biological evaluation. The analyzed compounds exhibit a diversified range of affinities for the µ opioid receptor (MOR), rather low δ opioid receptor (DOR) affinities, and no appreciable neurokinin-1 receptor binding. In three out of four pairs, N-acylhydrazone-based derivatives bind MOR better than their N’-acylhydrazide counterparts. The best of the novel derivatives have similar low nanomolar MOR binding affinity as the reference opioids, such as morphine and biphalin. The obtained order of MOR affinities was compared to the results of molecular docking. In vivo, four tested compounds turned out to be relatively strong analgesics. Finally, the NAH-based analogues reduce the number of melanoma cells in cell culture, while their N′-acylhydrazide counterparts do not. The antimelanoma properties are roughly correlated to the lipophilicity of the compounds.

Highlights

N-Acylhydrazone (NAH; otherwise termed hydrazide/hydrazone; Figure 1) has been identified as a “privileged structure” [1] that is a structural framework, which by being decorated with appropriate substituents is able to provide potent ligands for a variety of medicinally relevant molecular targets [2].A few marketed drugs contain the N-acylhydrazone motif in their structures, e.g., azumolene, carbazochrome, dantrolene, nitrofurantoin, nitrofurazone, nifuroxazide, testosterone 17-enanthate3-benzilic acid hydrazone [3]
The obtained compounds were analyzed on a Shimadzu LC-MS system (Shim-pol, Poland) with a Jupiter 4 μm Proteo 90 Å (250 × 4.6 mm, 4 μm) column using a solvent system containing 0.05% formic acid (FA) in water/acetonitrile
The presented research dealt with the question of how the C-terminal extension of short opioid peptide sequences influences the biological properties

Summary

Introduction

N-Acylhydrazone (NAH; otherwise termed hydrazide/hydrazone; Figure 1) has been identified as a “privileged structure” [1] that is a structural framework, which by being decorated with appropriate substituents is able to provide potent ligands for a variety of medicinally relevant molecular targets [2]. 3-benzilic acid hydrazone [3]. Further compounds of this type, for example PAC-1 (a procaspase activator with antitumour action), are being currently considered in clinical trials (NCT02355535). Numerous other NAHs have been described and tested at the preclinical level, with some of them. Numerous other NAHs have been described and tested at the preclinical level, Molecules. 2020, 25, 3429 with some of them having potential to reach the clinic. The reported activities of N-acylhydrazonebearing compounds include anti-inflammatory, analgesic, antithrombotic [4], antimicrobial [5,6], and having potential (apoptosis-inducing) to reach the clinic.

Methods

Results

Conclusion